Various diseases originate from defective genes that are either inherited or modified during life by environmental agents. Examples of these diseases include different forms of cystic fibrosis, Tay Sachs, sickle cell anemia, Duchenne muscular dystrophy, cancer, hemophilia, or LDL receptor deficiency. In addition, certain conditions are caused by the imbalance or lack of certain hormones or growth factors in the body stemming from damage to a particular organ. For example, kidney dialysis patients are often anemic because the damaged kidneys do not produce sufficient erythropoietin to adequately stimulate production of an appropriate level of red blood cells. Gene therapy or gene replacement therapy promises, not only a treatment, but also a potential cure for these diseases by replacing defective genes or by augmenting production of certain gene products.
Common vectors for introducing the therapeutic gene or nucleic acid include viral and non-viral vectors. Although viral delivery systems have been considered to be most efficient in delivering genes to cells, it may be limited because of a risk of triggering inflammatory or immunogenic responses. Forbes, S. J., “Review Article: Gene Therapy in Gastroenterology and Hepatology,” Ailment Pharmacol. Ther. 11:823–826 (1997). The risk is exemplified by the death of Jesse Gelsinger, a volunteer who died on Sep. 17, 1999 while participating in a gene therapy clinical trial at the Institute for Human Gene Therapy, University of Philadelphia. His death has fueled the controversy over the use and safety of gene therapy. The trial was directed to treat ornithine transcarbmylase (OTC) using a modified adenoviral vector. The administration, however, of the vector to Gelsinger “initiated an unusual and deadly immune-system response that led to multiple organ failure and death.” See Preliminary Findings, The Institute of Human Gene Therapy, University of Pennsylvania Health System, Dec. 2, 1999. Although adenoviral vectors offer several advantages over other viral vectors in that they can infect a wide range of cells and are not limited to replicating cells, as are retroviral vectors, adenoviral vectors may activate the immune system, as seen in the Gelsinger's case, such that the initial does or repeated introduction may become less effective, if not life threatening. See also Forbes, S. J., supra. Because other gene therapy vectors such as retrovirus or liposomes are generally foreign molecules, they similarly trigger the immune reaction and decrease the effectiveness of the therapy.
In addition to gene therapy, stem-cell based therapies are promising treatments for alleviating certain diseases such as neurodegenerative diseases, hematopoetic diseases and cancers, or muscular dystrophies. For these types of diseases, stem cells that have the ability to differentiate into a specific cell types may be grown in culture and transplanted into, for example, the central nervous system, the muscles, or the bone marrow to regenerate atrophied or ablated tissues. Current protocols for stem cell-based therapies are also disadvantageous because of the potential host immune response to the graft stem cells. In addition, it is also difficult to introduce a therapeutic gene into a human stem cell if such a therapeutic gene would be desirable.
Thus, there exists a need to enhance the safety and efficiency of gene therapy vectors that addresses the complexities of interacting with the immune system and the ease with which a therapeutic gene can be introduced into the body.